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Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product

Author

Listed:
  • Avanish Mishra

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Shih-Bo Huang

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Howard Hughes Medical Institute)

  • Taronish Dubash

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Risa Burr

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Jon F. Edd

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Ben S. Wittner

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Quinn E. Cunneely

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Victor R. Putaturo

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Akansha Deshpande

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Ezgi Antmen

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Kaustav A. Gopinathan

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Keisuke Otani

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Yoshiyuki Miyazawa

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Ji Eun Kwak

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Sara Y. Guay

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Justin Kelly

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • John Walsh

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Linda T. Nieman

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Isabella Galler

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • PuiYee Chan

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Michael S. Lawrence

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Ryan J. Sullivan

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Aditya Bardia

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    University of California)

  • Douglas S. Micalizzi

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Lecia V. Sequist

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Richard J. Lee

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Joseph W. Franses

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • David T. Ting

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Patricia A. R. Brunker

    (Massachusetts General Hospital and Harvard Medical School)

  • Shyamala Maheswaran

    (Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • David T. Miyamoto

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Daniel A. Haber

    (Massachusetts General Hospital Cancer Center and Harvard Medical School
    Howard Hughes Medical Institute
    Massachusetts General Hospital Cancer Center and Harvard Medical School)

  • Mehmet Toner

    (Massachusetts General Hospital and Harvard Medical School
    Shriners Children’s Boston)

Abstract

Circulating Tumor Cells (CTCs) in blood encompass DNA, RNA, and protein biomarkers, but clinical utility is limited by their rarity. To enable tumor epitope-agnostic interrogation of large blood volumes, we developed a high-throughput microfluidic device, depleting hematopoietic cells through high-flow channels and force-amplifying magnetic lenses. Here, we apply this technology to analyze patient-derived leukapheresis products, interrogating a mean blood volume of 5.83 liters from seven patients with metastatic cancer. High CTC yields (mean 10,057 CTCs per patient; range 100 to 58,125) reveal considerable intra-patient heterogeneity. CTC size varies within patients, with 67% overlapping in diameter with WBCs. Paired single-cell DNA and RNA sequencing identifies subclonal patterns of aneuploidy and distinct signaling pathways within CTCs. In prostate cancers, a subpopulation of small aneuploid cells lacking epithelial markers is enriched for neuroendocrine signatures. Pooling of CNV-confirmed CTCs enables whole exome sequencing with high mutant allele fractions. High-throughput CTC enrichment thus enables cell-based liquid biopsy for comprehensive monitoring of cancer.

Suggested Citation

  • Avanish Mishra & Shih-Bo Huang & Taronish Dubash & Risa Burr & Jon F. Edd & Ben S. Wittner & Quinn E. Cunneely & Victor R. Putaturo & Akansha Deshpande & Ezgi Antmen & Kaustav A. Gopinathan & Keisuke , 2025. "Tumor cell-based liquid biopsy using high-throughput microfluidic enrichment of entire leukapheresis product," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55140-x
    DOI: 10.1038/s41467-024-55140-x
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